Introduction: Multiple sclerosis is one the most common diseases of the central nervous system. Fatigue and depression are common symptoms of the disorder. The identification of the factors associated with fatigue can help to solve this problem and subsequently, reduce the problems of these patients.

Objective: This study aimed to determine the predictor role of depression in patients with multiple sclerosis fatigue.

Materials and Methods: This is a cross-sectional, descriptive and analytical study. The study was carried out in the special diseases centre of Kerman University of Medical Sciences. In this study, 170 patients with multiple sclerosis were enrolled, by using available sampling in 2014. In order to collect the data, three demographic questionnaires, the Fatigue Severity questionnaire (FSS = Fatigue Severity Scale) and Zung Depression were used. The validity and reliability of the instruments had been confirmed in Iran. The data was analyzed by using descriptive and analytical statistics (chi-square regression multivariate logistic).

Results: In the study, 75.3% of participants were women and 24.7% were men. Of them, 70% were married and 21.8% were single. Additionally, the results of this study showed that 65.3% of the participants complained of fatigue and 51.8% had depression. The results of the regression showed that the risk of fatigue in people who suffer from depression is 2.75 times than those who do not have depression (p < 0.002, CI 95%: 1.43-5.30).

Conclusion: The results of this study revealed that depression can predict the onset of fatigue in patients with multiple sclerosis. It is necessary to reduce and control the symptoms of depression, which is a symptom of multiple sclerosis. Accordingly, fatigue as a common symptom in patients can be reduced, resulting in a higher quality of life in this chronic disease.